Clinical Trials Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in practice.

Treatment Studies in Adult and Adolescent Subjects (13
years of age and older)

A total of 1171 subjects who participated in adult
controlled clinical trials for the treatment of influenza were treated with
TAMIFLU. The most frequently reported adverse events in these studies were
nausea and vomiting. These events were generally of mild to moderate severity
and usually occurred on the first 2 days of administration. Less than 1% of
subjects discontinued prematurely from clinical trials due to nausea and
vomiting.

Adverse events that occurred with an incidence of 1% or
greater in 1440 subjects taking placebo or TAMIFLU 75 mg twice daily in adult
treatment studies are shown in Table 6. This summary includes 945 healthy young
adults and 495 “at risk” subjects (elderly patients and patients with chronic
cardiac or respiratory disease). Those events reported numerically more
frequently in subjects taking TAMIFLU compared with placebo were nausea,
vomiting, bronchitis, insomnia, and vertigo.

Prophylaxis Studies in Adult and Adolescent Subjects (13
years of age and older)

A total of 4187 subjects (adolescents, healthy adults,
and elderly) participated in prophylaxis studies, of whom 1790 received the
recommended dose of 75 mg once daily for up to 6 weeks. Adverse events were
qualitatively very similar to those seen in the treatment studies, despite a
longer duration of dosing (see Table 6). Events reported more frequently in
subjects receiving TAMIFLU compared to subjects receiving placebo in
prophylaxis studies, and more commonly than in treatment studies, were aches
and pains, rhinorrhea, dyspepsia and upper respiratory tract infections.
However, the difference in incidence between TAMIFLU and placebo for these
events was less than 1%. There were no clinically relevant differences in the
safety profile of the 942 elderly subjects who received TAMIFLU or placebo,
compared with the younger population.

Table 6 : Most Frequent Adverse Events in Studies in
Naturally Acquired Influenza in Subjects 13 Years of Age and Older

Adverse Event*

Treatment

Prophylaxis

Placebo
N=716

TAMIFLU 75 mg twice daily
N=724

Placebo/ No Prophylaxis†
N=1688

TAMIFLU 75 mg once daily
N=1790

Nausea (without vomiting)

40 (6%)

72 (10%)

56(3%)

129 (7%)

Vomiting

21 (3%)

68 (9%)

16 (1%)

39 (2%)

Diarrhea

70 (10%)

48 (7%)

40 (2%)

50 (3%)

Bronchitis

15 (2%)

17 (2%)

22 (1%)

15 (1%)

Abdominal pain

16 (2%)

16 (2%)

25 (1%)

37 (2%)

Dizziness

25 (3%)

15 (2%)

21 (1%)

24 (1%)

Headache

14 (2%)

13 (2%)

306 (18%)

326 (18%)

Cough

12 (2%)

9 (1%)

119 (7%)

94 (5%)

Insomnia

6 (1%)

8 (1%)

15 (1%)

22 (1%)

Vertigo

4 (1%)

7 (1%)

4 ( < 1%)

4 ( < 1%)

Fatigue

7 (1%)

7 (1%)

163 (10%)

139 (8%)

* Adverse events included are all events reported in the
treatment studies with frequency ≥ 1%
in the TAMIFLU 75 mg twice daily group.
† The majority of subjects received placebo; 254
subjects from a randomized, open-label postexposure prophylaxis study in
households did not receive placebo or prophylaxis therapy.

Treatment Studies in Pediatric
Subjects (1 to 12 years of age)

A total of 1032 pediatric
subjects aged 1 to 12 years (including 698 otherwise healthy pediatric subjects
aged 1 to 12 years and 334 asthmatic pediatric subjects aged 6 to 12 years)
participated in controlled clinical trials of TAMIFLU given for the treatment
of influenza. A total of 515 pediatric subjects received treatment with TAMIFLU
for oral suspension.

Adverse events occurring in 1%
or greater of pediatric subjects receiving TAMIFLU treatment are listed in
Table 7. The most frequently reported adverse event was vomiting. Other events
reported more frequently by pediatric subjects treated with TAMIFLU included
abdominal pain, epistaxis, ear disorder, and conjunctivitis. These events
generally occurred once and resolved despite continued dosing resulting in
discontinuation of drug in 8 out of 515 (2%) cases.

The adverse event profile in
adolescents is similar to that described for adult subjects and pediatric
subjects aged 1 to 12 years.

Prophylaxis Studies in Pediatric Subjects (1 to 12 years
of age)

Pediatric subjects aged 1 to 12 years participated in a
postexposure prophylaxis study in households, both as index cases (n=134) and
as contacts (n=222). Gastrointestinal events were the most frequent,
particularly vomiting. In a separate 6-week, uncontrolled, pediatric seasonal
prophylaxis study (n=49), the adverse events noted were consistent with those
previously observed (see Table 7).

Table 7 : Most Frequent Adverse Events Occurring in
Children Aged 1 to 12 Years in Studies in Naturally Acquired Influenza

Adverse Event1

Treatment Trials*

Household Prophylaxis Trialf

Placebo
N=517

TAMIFLU 2 mg/kg twice daily
N=515

No Prophylaxis§
N=87

Prophylaxis with TAMIFLU once daily§
N=99

Vomiting

48(9%)

77(15%)

2(2%)

10(10%)

Diarrhea

55(11%)

49(10%)

-

1(1%)

Otitis media

58(11%)

45(9%)

2(2%)

2(2%)

Abdominal pain

20(4%)

24(5%)

-

3(3%)

Asthma (including aggravated)

19(4%)

18(3%)

1(1%)

1(1%)

Nausea

22(4%)

17(3%)

1(1%)

4(4%)

Epistaxis

13(3%)

16(3%)

-

1(1%)

Pneumonia

17(3%)

10(2%)

2(2%)

-

Ear disorder

6(1%)

9(2%)

-

-

Sinusitis

13(3%)

9(2%)

-

-

Bronchitis

11(2%)

8(2%)

2(2%)

-

Conjunctivitis

2( < 1%)

5(1%)

-

-

Dermatitis

10(2%)

5(1%)

-

-

Lymphadenopathy

8(2%)

5(1%)

-

-

Tympanic membrane disorder

6(1%)

5(1%)

-

-

* Pooled data from trials of
TAMIFLU treatment of naturally acquired influenza.
† A randomized, open-label study of household transmission in which
household contacts received either prophylaxis or no prophylaxis but treatment
if they became ill. Only contacts who received prophylaxis or who remained on
no prophylaxis are included in this table.
‡ Adverse events included in Table 7 are all events
reported in the treatment studies with frequency ≥ 1% in
the TAMIFLU 75 mg twice daily group.
§ Unit dose = age-based dosing of 30 mg, 45 mg, or 60 mg

Treatment Studies in Pediatric
Subjects (2 weeks to less than 1 year of age)

Assessment of adverse reactions
is based on two open label studies that included safety data on 135 influenza-infected
subjects 2 weeks to less than 1 year of age (including premature infants at
least 36 weeks post conceptional age) exposed to TAMIFLU at doses ranging from
2 to 3.5 mg/kg twice daily for 5 days. The safety profile was similar across
the age range studied, with vomiting, diarrhea and diaper rash being the most
frequently reported adverse reactions. The safety profile observed in subjects
2 weeks to less than 1 year of age was consistent with the established safety
profile of adults and pediatric subjects older than 1 year of age.

Prophylaxis Study in
Immunocompromised Subjects

In a 12-week seasonal
prophylaxis study in 475 immunocompromised subjects, including 18 pediatric
subjects 1 to 12 years of age, the safety profile in the 238 subjects receiving
TAMIFLU was consistent with that previously observed in other TAMIFLU
prophylaxis clinical trials.

Postmarketing Experience

The following adverse reactions have been identified
during postapproval use of TAMIFLU. Because these reactions are reported
voluntarily from a population of uncertain size, it is not possible to reliably
estimate their frequency or establish a causal relationship to TAMIFLU
exposure.

Body as a Whole: Swelling of the face or tongue,
allergy, anaphylactic/anaphylactoid reactions, hypothermia

DRUG INTERACTIONS

Influenza Vaccines

The concurrent use of TAMIFLU with live attenuated
influenza vaccine (LAIV) intranasal has not been evaluated. However, because of
the potential for interference between these products, LAIV should not be
administered within 2 weeks before or 48 hours after administration of TAMIFLU,
unless medically indicated. The concern about possible interference arises from
the potential for antiviral drugs to inhibit replication of live vaccine virus.
Trivalent inactivated influenza vaccine can be administered at any time
relative to use of TAMIFLU.

Overall Drug Interaction Profile for Oseltamivir

Oseltamivir is extensively converted to oseltamivir
carboxylate by esterases, located predominantly in the liver. Drug interactions
involving competition for esterases have not been extensively reported in
literature. Low protein binding of oseltamivir and oseltamivir carboxylate
suggests that the probability of drug displacement interactions is low.

In vitro studies demonstrate that neither oseltamivir nor
oseltamivir carboxylate is a good substrate for P450 mixed-function oxidases or
for glucuronyl transferases.

Clinically important drug interactions involving
competition for renal tubular secretion are unlikely due to the known safety
margin for most of these drugs, the elimination characteristics of oseltamivir
carboxylate (glomerular filtration and anionic tubular secretion) and the
excretion capacity of these pathways. Coadministration of probenecid results in
an approximate two-fold increase in exposure to oseltamivir carboxylate due to
a decrease in active anionic tubular secretion in the kidney. However, due to
the safety margin of oseltamivir carboxylate, no dose adjustments are required
when coadministering with probenecid.

No pharmacokinetic interactions have been observed when
coadministering oseltamivir with amoxicillin, acetaminophen, aspirin,
cimetidine, antacids (magnesium and aluminum hydroxides and calcium
carbonates), or warfarin.